Tetrahydrocannabinol: Difference between revisions

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In April 2014 the [[American Academy of Neurology]] published a systematic review of the efficacy and safety of medical marijuana and marijuana-derived products in certain neurological disorders.<ref name="AAN">{{cite journal | author = Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D | title = Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology | journal = Neurology | volume = 82 | issue = 17 | pages = 1556–63 |date=April 2014 | pmid = 24778283 | doi = 10.1212/WNL.0000000000000363 | url = }}</ref> The review identified 34 studies meeting inclusion criteria, of which 8 were rated as Class I quality. The study found evidence supporting the effectiveness of cannabis extracts and THC in treating certain symptoms of multiple sclerosis, but found insufficient evidence to determine the effectiveness of cannabis products in treating several other neurological diseases.
In April 2014 the [[American Academy of Neurology]] published a systematic review of the efficacy and safety of medical marijuana and marijuana-derived products in certain neurological disorders.<ref name="AAN">{{cite journal | author = Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D | title = Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology | journal = Neurology | volume = 82 | issue = 17 | pages = 1556–63 | date = April 2014 | pmid = 24778283 | doi = 10.1212/WNL.0000000000000363 | url = }}</ref> The review identified 34 studies meeting inclusion criteria, of which 8 were rated as Class I quality. The study found evidence supporting the effectiveness of cannabis extracts and THC in treating certain symptoms of multiple sclerosis, but found insufficient evidence to determine the effectiveness of cannabis products in treating several other neurological diseases.


===Multiple sclerosis symptoms===
===Multiple sclerosis symptoms===
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::''Parkinson disease''. Based on a single study, oral cannabis extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson disease.<ref name="AAN"/>
::''Parkinson disease''. Based on a single study, oral cannabis extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson disease.<ref name="AAN"/>


::''Alzheimer's disease''. A 2011 Cochrane Review found insufficient evidence to conclude whether cannabis products have any utility in the treatment of Alzheimer's disease.<ref>{{cite pmid|19370677}}</ref>
::''Alzheimer's disease''. A 2011 Cochrane Review found insufficient evidence to conclude whether cannabis products have any utility in the treatment of Alzheimer's disease.<ref>{{cite journal | author = Krishnan S, Cairns R, Howard R | title = Cochrane Database of Systematic Reviews | journal = Cochrane database of systematic reviews (Online) | issue = 2 | pages = CD007204 | year = 2009 | pmid = 19370677 | doi = 10.1002/14651858.CD007204.pub2 | chapter = Cannabinoids for the treatment of dementia | editor1-last = Krishnan | editor1-first = Sarada }}</ref>


===Other neurological disorders===
===Other neurological disorders===
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=== Other studies in humans ===
=== Other studies in humans ===
Evidence suggests that THC helps alleviate symptoms suffered both by [[AIDS]] patients, and by cancer patients undergoing [[chemotherapy]], by increasing appetite and decreasing nausea.<ref>{{cite web|url=http://www.cancer.gov/cancertopics/pdq/cam/cannabis/patient/page2 |title=Cannabis and Cannabinoids |publisher=National Cancer Institute |accessdate=12 January 2014}}</ref><ref name=Haney>{{cite journal | author = Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, Foltin RW | title = Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 45 | issue = 5 | pages = 545–54 | year = 2007 | pmid = 17589370 | doi = 10.1097/QAI.0b013e31811ed205 | last5 = Vosburg | first4 = Carl L | first5 = Suzanne K | last4 = Hart | last7 = Foltin | last6 = Comer | first6 = Sandra D | first7 = Richard W }}</ref><ref>{{cite journal | author = Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Bacchetti P, McCune JM, Schambelan M | title = Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial | journal = Annals of Internal Medicine | volume = 139 | issue = 4 | pages = 258–66 | year = 2003 | pmid = 12965981 | doi = 10.7326/0003-4819-139-4-200308190-00008 | first11 = SG | first10 = JA }}</ref><ref name="groten">{{cite book|editor-last=Grotenhermen |editor-first=Franjo |editor2-last=Russo |editor2-first=Ethan |chapter=Review of Therapeutic Effects |chapterurl=http://books.google.com/books?id=JvIyVk2IL_sC&pg=PA124 |title=Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential |publisher=Psychology Press |location=New York City |year=2002 |isbn=978-0-7890-1508-2 |page=124 |quote=The only approved preparations to date, Marinol (dronabinol, Δ<sup>9</sup>-THC) and Cesamet (nabilone), are approved for the indication of nausea and vomiting associated with cancer chemotherapy. Marinol is also approved for anorexia and cachexia in HIV/AIDS.}}</ref> It has also been shown to assist some [[glaucoma]] patients{{Citation needed|date=May 2014}} by reducing pressure within the eye, and is used in the form of cannabis by a number of [[multiple sclerosis]] patients, who use it to alleviate [[neuropathic pain]] and [[spasticity]]. The [[National Multiple Sclerosis Society]] is currently supporting further research into these uses.<ref name="MS society">{{cite web|url=http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/treatments/complementary--alternative-medicine/marijuana/index.aspx |title=Marijuana (Cannabis) |publisher=National Multiple Sclerosis Society |accessdate=5 September 2009}}</ref> Studies in humans have been limited by federal and state laws criminalizing marijuana.
Evidence suggests that THC helps alleviate symptoms suffered both by [[AIDS]] patients, and by cancer patients undergoing [[chemotherapy]], by increasing appetite and decreasing nausea.<ref>{{cite web|url=http://www.cancer.gov/cancertopics/pdq/cam/cannabis/patient/page2 |title=Cannabis and Cannabinoids |publisher=National Cancer Institute |accessdate=12 January 2014}}</ref><ref name=Haney>{{cite journal | author = Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, Foltin RW | title = Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 45 | issue = 5 | pages = 545–54 | year = 2007 | pmid = 17589370 | doi = 10.1097/QAI.0b013e31811ed205 }}</ref><ref>{{cite journal | author = Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, Benowitz NL, Bredt BM, Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Bacchetti P, McCune JM, Schambelan M | title = Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial | journal = Annals of Internal Medicine | volume = 139 | issue = 4 | pages = 258–66 | year = 2003 | pmid = 12965981 | doi = 10.7326/0003-4819-139-4-200308190-00008 | first11 = SG | first10 = JA }}</ref><ref name="groten">{{cite book|editor-last=Grotenhermen |editor-first=Franjo |editor2-last=Russo |editor2-first=Ethan |chapter=Review of Therapeutic Effects |chapterurl=http://books.google.com/books?id=JvIyVk2IL_sC&pg=PA124 |title=Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential |publisher=Psychology Press |location=New York City |year=2002 |isbn=978-0-7890-1508-2 |page=124 |quote=The only approved preparations to date, Marinol (dronabinol, Δ<sup>9</sup>-THC) and Cesamet (nabilone), are approved for the indication of nausea and vomiting associated with cancer chemotherapy. Marinol is also approved for anorexia and cachexia in HIV/AIDS.}}</ref> It has also been shown to assist some [[glaucoma]] patients{{Citation needed|date=May 2014}} by reducing pressure within the eye, and is used in the form of cannabis by a number of [[multiple sclerosis]] patients, who use it to alleviate [[neuropathic pain]] and [[spasticity]]. The [[National Multiple Sclerosis Society]] is currently supporting further research into these uses.<ref name="MS society">{{cite web|url=http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/treatments/complementary--alternative-medicine/marijuana/index.aspx |title=Marijuana (Cannabis) |publisher=National Multiple Sclerosis Society |accessdate=5 September 2009}}</ref> Studies in humans have been limited by federal and state laws criminalizing marijuana.


In August 2009 a [[Clinical study#Phase IV|phase IV clinical trial]] by the [[Hadassah Medical Center]] in Jerusalem, Israel started to investigate the effects of THC on [[post-traumatic stress disorder]]s.<ref name="urlAdd on Study on Δ9-THC Treatment for Posttraumatic Stress Disorders (PTSD) – Full Text View – ClinicalTrials.gov">{{ClinicalTrialsGov|NCT00965809|Add on Study on Δ9-THC Treatment for Posttraumatic Stress Disorders (PTSD) (THC_PTSD)}}</ref>
In August 2009 a [[Clinical study#Phase IV|phase IV clinical trial]] by the [[Hadassah Medical Center]] in Jerusalem, Israel started to investigate the effects of THC on [[post-traumatic stress disorder]]s.<ref name="urlAdd on Study on Δ9-THC Treatment for Posttraumatic Stress Disorders (PTSD) – Full Text View – ClinicalTrials.gov">{{ClinicalTrialsGov|NCT00965809|Add on Study on Δ9-THC Treatment for Posttraumatic Stress Disorders (PTSD) (THC_PTSD)}}</ref>
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=== Studies in animals and in vitro ===
=== Studies in animals and in vitro ===
A two-year study in which rats and mice were force-fed tetrahydrocannabinol dissolved in corn oil showed reduced body mass, enhanced survival rates, and decreased tumor incidences in several sites, mainly organs under hormonal control. It also caused [[testicular atrophy]] and uterine and ovarian [[hypoplasia]], as well as hyperactivity and convulsions immediately after administration, of which the onset and frequency were dose related.<ref>{{cite journal | author = Chan PC, Sills RC, Braun AG, Haseman JK, Bucher JR | title = Toxicity and Carcinogenicity of Δ9-Tetrahydrocannabinol in Fischer Rats and B6C3F1 Mice | journal = Fundamental and Applied Toxicology | volume = 30 | issue = 1 | pages = 109–17 | year = 1996 | pmid = 8812248 | doi = 10.1006/faat.1996.0048 | first4 = JK | first2 = RC | first5 = JR | first3 = AG }}</ref>
A two-year study in which rats and mice were force-fed tetrahydrocannabinol dissolved in corn oil showed reduced body mass, enhanced survival rates, and decreased tumor incidences in several sites, mainly organs under hormonal control. It also caused [[testicular atrophy]] and uterine and ovarian [[hypoplasia]], as well as hyperactivity and convulsions immediately after administration, of which the onset and frequency were dose related.<ref>{{cite journal | author = Chan PC, Sills RC, Braun AG, Haseman JK, Bucher JR | title = Toxicity and Carcinogenicity of Δ9-Tetrahydrocannabinol in Fischer Rats and B6C3F1 Mice | journal = Fundamental and Applied Toxicology | volume = 30 | issue = 1 | pages = 109–17 | year = 1996 | pmid = 8812248 | doi = 10.1006/faat.1996.0048 }}</ref>


Research in rats indicates that THC prevents [[hydroperoxide]]-induced [[oxidative damage]] as well as or better than other [[antioxidant]]s in a chemical ([[Fenton reaction]]) system and [[neuron]]al cultures.<ref name="pmid9653176">{{cite journal | author = Hampson AJ, Grimaldi M, Axelrod J, Wink D | title = Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants | journal = Proceedings of the National Academy of Sciences | volume = 95 | issue = 14 | pages = 8268–73 | year = 1998 | pmid = 9653176 | pmc = 20965 | doi = 10.1073/pnas.95.14.8268 | bibcode = 1998PNAS...95.8268H }}</ref> In mice low doses of Δ<sup>9</sup>-THC reduces the progression of [[atherosclerosis]].<ref name="pmid15815632">{{cite journal | author = Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard JL, Mach F | title = Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice | journal = Nature | volume = 434 | issue = 7034 | pages = 782–6 | year = 2005 | pmid = 15815632 | doi = 10.1038/nature03389 | first8 = Jean-Louis | first4 = Graziano | first2 = Niels R. | first5 = Fabienne | first9 = François | bibcode = 2005Natur.434..782S | first10 = F | first3 = Claire | first6 = Christian | first7 = Andreas }}</ref>
Research in rats indicates that THC prevents [[hydroperoxide]]-induced [[oxidative damage]] as well as or better than other [[antioxidant]]s in a chemical ([[Fenton reaction]]) system and [[neuron]]al cultures.<ref name="pmid9653176">{{cite journal | author = Hampson AJ, Grimaldi M, Axelrod J, Wink D | title = Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants | journal = Proceedings of the National Academy of Sciences | volume = 95 | issue = 14 | pages = 8268–73 | year = 1998 | pmid = 9653176 | pmc = 20965 | doi = 10.1073/pnas.95.14.8268 | bibcode = 1998PNAS...95.8268H }}</ref> In mice low doses of Δ<sup>9</sup>-THC reduces the progression of [[atherosclerosis]].<ref name="pmid15815632">{{cite journal | author = Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard JL, Mach F | title = Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice | journal = Nature | volume = 434 | issue = 7034 | pages = 782–6 | year = 2005 | pmid = 15815632 | doi = 10.1038/nature03389 | bibcode = 2005Natur.434..782S | first3 = Claire }}</ref>


Instead, recent studies with synthetic cannabinoids show that activation of CB1 receptors can facilitate [[neurogenesis]],<ref name=Jiang2005>{{cite journal | author = Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X | title = Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects | journal = Journal of Clinical Investigation | volume = 115 | issue = 11 | pages = 3104–3116 | year = 2005 | pmid = 16224541 | pmc = 1253627 | doi = 10.1172/JCI25509 | first4 = J | first2 = Y | first5 = SP | first3 = L | first6 = G | first7 = X }}</ref> as well as neuroprotection, in animals<ref name=Sarne2005>{{cite journal | author = Sarne Y, Mechoulam R | title = Cannabinoids: between neuroprotection and neurotoxicity | journal = Curr Drug Targets CNS Neurol Disord | volume = 4 | issue = 6 | pages = 677–84 |date=December 2005 | pmid = 16375685 | doi = 10.2174/156800705774933005 }}</ref> This, along with research into the CB2 receptor (throughout the immune system), has given the case for medical marijuana more support.<ref name=Correa2005>{{cite journal | author = Correa F, Mestre L, Molina-Holgado E, Arévalo-Martín A, Docagne F, Romero E, Molina-Holgado F, Borrell J, Guaza C | title = The Role of Cannabinoid System on Immune Modulation: Therapeutic Implications on CNS Inflammation | journal = Mini Reviews in Medicinal Chemistry | volume = 5 | issue = 7 | pages = 671–675 | year = 2005 | pmid = 16026313 | doi = 10.2174/1389557054368790 | first8 = Jose | first4 = Angel | first2 = Leyre | first5 = Fabian | first9 = Carmen | first3 = Eduardo | first6 = Eva | first7 = Francisco }}</ref><ref name="Fernández-ruiz2007">{{cite journal | author = Fernández-Ruiz J, Romero J, Velasco G, Tolón RM, Ramos JA, Guzmán M | title = Cannabinoid CB2 receptor: a new target for controlling neural cell survival? | journal = Trends in Pharmacological Sciences | volume = 28 | issue = 1 | pages = 39–45 | year = 2007 | pmid = 17141334 | doi = 10.1016/j.tips.2006.11.001 | first4 = Rosa M. | first2 = Julián | first5 = José A. | first3 = Guillermo | first6 = Manuel }}</ref> THC is both a CB1 and CB2 agonist.<ref>{{cite web|first=RG |last=Pertwee |url=http://www.tocris.com/pdfs/pdf_downloads/Cannabinoid_Receptor_Ligands_Review.pdf |title=Cannabinoid Receptor Ligands |publisher=Tocris |year=2010 |accessdate=20 April 2011}}</ref>
Instead, recent studies with synthetic cannabinoids show that activation of CB1 receptors can facilitate [[neurogenesis]],<ref name=Jiang2005>{{cite journal | author = Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X | title = Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects | journal = Journal of Clinical Investigation | volume = 115 | issue = 11 | pages = 3104–3116 | year = 2005 | pmid = 16224541 | pmc = 1253627 | doi = 10.1172/JCI25509 }}</ref> as well as neuroprotection, in animals<ref name=Sarne2005>{{cite journal | author = Sarne Y, Mechoulam R | title = Cannabinoids: between neuroprotection and neurotoxicity | journal = Curr Drug Targets CNS Neurol Disord | volume = 4 | issue = 6 | pages = 677–84 | date = December 2005 | pmid = 16375685 | doi = 10.2174/156800705774933005 }}</ref> This, along with research into the CB2 receptor (throughout the immune system), has given the case for medical marijuana more support.<ref name=Correa2005>{{cite journal | author = Correa F, Mestre L, Molina-Holgado E, Arévalo-Martín A, Docagne F, Romero E, Molina-Holgado F, Borrell J, Guaza C | title = The Role of Cannabinoid System on Immune Modulation: Therapeutic Implications on CNS Inflammation | journal = Mini Reviews in Medicinal Chemistry | volume = 5 | issue = 7 | pages = 671–675 | year = 2005 | pmid = 16026313 | doi = 10.2174/1389557054368790 }}</ref><ref name="Fernández-ruiz2007">{{cite journal | author = Fernández-Ruiz J, Romero J, Velasco G, Tolón RM, Ramos JA, Guzmán M | title = Cannabinoid CB2 receptor: a new target for controlling neural cell survival? | journal = Trends in Pharmacological Sciences | volume = 28 | issue = 1 | pages = 39–45 | year = 2007 | pmid = 17141334 | doi = 10.1016/j.tips.2006.11.001 }}</ref> THC is both a CB1 and CB2 agonist.<ref>{{cite web|first=RG |last=Pertwee |url=http://www.tocris.com/pdfs/pdf_downloads/Cannabinoid_Receptor_Ligands_Review.pdf |title=Cannabinoid Receptor Ligands |publisher=Tocris |year=2010 |accessdate=20 April 2011}}</ref>


==Adverse effects==
==Adverse effects==


===Acute toxicity===
===Acute toxicity===
There has never been a documented human fatality solely from overdosing on tetrahydrocannabinol or cannabis in its natural form.<ref name="Walker and Huang">{{cite journal | author = Walker JM, Huang SM | title = Cannabinoid analgesia | journal = Pharmacol. Ther. | volume = 95 | issue = 2 | pages = 127–35 |date=August 2002 | pmid = 12182960 | doi = 10.1016/S0163-7258(02)00252-8 | quote = ...to date, there are no deaths known to have resulted from overdose of cannabis. (p. 128) }}</ref> However, numerous reports have suggested an association of cannabis smoking with an increased risk of [[myocardial infarction]].<ref>{{cite journal | author = Thomas G, Kloner RA, Rezkalla S | title = Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know | journal = Am. J. Cardiol. | volume = 113 | issue = 1 | pages = 187–90 | date = January 2014 | pmid = 24176069 | doi = 10.1016/j.amjcard.2013.09.042 | url = }}</ref><ref>{{cite journal | author = Aryana A, Williams MA | title = Marijuana as a trigger of cardiovascular events: speculation or scientific certainty? | journal = Int. J. Cardiol. | volume = 118 | issue = 2 | pages = 141–4 | date = May 2007 | pmid = 17005273 | doi = 10.1016/j.ijcard.2006.08.001 }}</ref> Information about the [[toxicity]] of THC is primarily based on results from animal studies. The toxicity depends on the route of administration and the laboratory animal.
There has never been a documented human fatality solely from overdosing on tetrahydrocannabinol or cannabis in its natural form.<ref name="Walker and Huang">{{cite journal | author = Walker JM, Huang SM | title = Cannabinoid analgesia | journal = Pharmacol. Ther. | volume = 95 | issue = 2 | pages = 127–35 | date = August 2002 | pmid = 12182960 | doi = 10.1016/S0163-7258(02)00252-8 | quote = ...to date, there are no deaths known to have resulted from overdose of cannabis. (p. 128) }}</ref> However, numerous reports have suggested an association of cannabis smoking with an increased risk of [[myocardial infarction]].<ref>{{cite journal | author = Thomas G, Kloner RA, Rezkalla S | title = Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know | journal = Am. J. Cardiol. | volume = 113 | issue = 1 | pages = 187–90 | date = January 2014 | pmid = 24176069 | doi = 10.1016/j.amjcard.2013.09.042 | url = }}</ref><ref>{{cite journal | author = Aryana A, Williams MA | title = Marijuana as a trigger of cardiovascular events: speculation or scientific certainty? | journal = Int. J. Cardiol. | volume = 118 | issue = 2 | pages = 141–4 | date = May 2007 | pmid = 17005273 | doi = 10.1016/j.ijcard.2006.08.001 }}</ref> Information about the [[toxicity]] of THC is primarily based on results from animal studies. The toxicity depends on the route of administration and the laboratory animal.


The estimated lethal dose of intravenous dronabinol in humans is 30&nbsp;mg/kg,<ref name="American Health Packaging">{{cite web|title=DRONABINOL capsule [American Health Packaging] |url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=68b4168b-5782-4e68-a25a-5b4e4408dbce |work=National Library of Medicine |publisher=Daily Med |accessdate=12 January 2014 |author=<!--Staff editor(s); no by-line--> |date=July 2012 |quote=The estimated lethal human dose of intravenous dronabinol is 30&nbsp;mg/kg (2100 mg/70 kg). Significant CNS symptoms in antiemetic studies followed oral doses of 0.4&nbsp;mg/kg (28&nbsp;mg/70&nbsp;kg) of dronabinol capsules.}}</ref> meaning lethality is unlikely. The typical medicinal dosage administered is two 2.5&nbsp;mg capsules daily; for an 80&nbsp;kg man (~170&nbsp;lb). A lethal dose for such a person would be 960 of those capsules infused intravenously. Non-fatal overdoses have occurred: "Significant CNS symptoms in antiemetic studies followed oral doses of 0.4&nbsp;mg/kg (28&nbsp;mg/70&nbsp;kg) of dronabinol capsules."<ref name="American Health Packaging" />
The estimated lethal dose of intravenous dronabinol in humans is 30&nbsp;mg/kg,<ref name="American Health Packaging">{{cite web|title=DRONABINOL capsule [American Health Packaging] |url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=68b4168b-5782-4e68-a25a-5b4e4408dbce |work=National Library of Medicine |publisher=Daily Med |accessdate=12 January 2014 |author=<!--Staff editor(s); no by-line--> |date=July 2012 |quote=The estimated lethal human dose of intravenous dronabinol is 30&nbsp;mg/kg (2100 mg/70 kg). Significant CNS symptoms in antiemetic studies followed oral doses of 0.4&nbsp;mg/kg (28&nbsp;mg/70&nbsp;kg) of dronabinol capsules.}}</ref> meaning lethality is unlikely. The typical medicinal dosage administered is two 2.5&nbsp;mg capsules daily; for an 80&nbsp;kg man (~170&nbsp;lb). A lethal dose for such a person would be 960 of those capsules infused intravenously. Non-fatal overdoses have occurred: "Significant CNS symptoms in antiemetic studies followed oral doses of 0.4&nbsp;mg/kg (28&nbsp;mg/70&nbsp;kg) of dronabinol capsules."<ref name="American Health Packaging" />
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Its status as an illegal drug in most countries can make research difficult; for instance in the United States where the [[National Institute on Drug Abuse]] was the only legal source of cannabis for researchers until it recently became legalized in Colorado and Washington state.<ref name="MAPS">{{cite web|url=http://www.maps.org/research/mmj/ |title=Medical Marijuana |publisher=Multidisciplinary Association for Psychoactive Substances |accessdate=12 January 2014}}</ref>
Its status as an illegal drug in most countries can make research difficult; for instance in the United States where the [[National Institute on Drug Abuse]] was the only legal source of cannabis for researchers until it recently became legalized in Colorado and Washington state.<ref name="MAPS">{{cite web|url=http://www.maps.org/research/mmj/ |title=Medical Marijuana |publisher=Multidisciplinary Association for Psychoactive Substances |accessdate=12 January 2014}}</ref>


A 2011 systematic review evaluated published studies of the acute and long-term cognitive effects of cannabis. THC intoxication is well established to impair cognitive functioning on an acute basis, including effects on the ability to plan, organize, solve problems, make decisions, and control impulses. The extent of this impact may be greater in novice users, and paradoxically, those habituated to high level ingestion may have reduced cognition during withdrawal. Studies of long-term effects on cognition have provided conflicting results, with some studies finding no difference between long-term abstainers and never-users and others finding long term deficits. The discrepancies between studies may reflect greater long term effects among heavier users relative to occasional users, and greater duration of effect among those with heavy use as adolescents compared to later in life.<ref>{{cite journal | author = Crean RD, Crane NA, Mason BJ | title = An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions | journal = J Addict Med | volume = 5 | issue = 1 | pages = 1–8 |date=March 2011 | pmid = 21321675 | pmc = 3037578 | doi = 10.1097/ADM.0b013e31820c23fa | url = }}</ref> A second systematic review focused on neuroimaging studies found little evidence supporting an effect of cannabis use on brain structure and function.<ref>{{cite journal | author = Martín-Santos R, Fagundo AB, Crippa JA, Atakan Z, Bhattacharyya S, Allen P, Fusar-Poli P, Borgwardt S, Seal M, Busatto GF, McGuire P | title = Neuroimaging in cannabis use: a systematic review of the literature | journal = Psychol Med | volume = 40 | issue = 3 | pages = 383–98 |date=March 2010 | pmid = 19627647 | doi = 10.1017/S0033291709990729 | url = }}</ref> A 2003 meta analysis concluded that any long term cognitive effects were relatively modest in magnitude and limited to certain aspects of learning and memory.<ref>{{cite journal|doi=10.1017/S1355617703950016 |laysummary=http://www.webmd.com/mental-health/news/20030701/heavy-marijuana-use-doesnt-damage-brain |laysource=[[WebMD]] |laydate=1 July 2003 |title=Non-acute (residual) neurocognitive effects of cannabis use: A meta-analytic study |year=2003 |last=Grant |first=I |journal=Journal of the International Neuropsychological Society |volume=9 |issue=5 |first2=Raul |first3=Catherine L. |first4=Loki |first5=Tanya}}</ref>
A 2011 systematic review evaluated published studies of the acute and long-term cognitive effects of cannabis. THC intoxication is well established to impair cognitive functioning on an acute basis, including effects on the ability to plan, organize, solve problems, make decisions, and control impulses. The extent of this impact may be greater in novice users, and paradoxically, those habituated to high level ingestion may have reduced cognition during withdrawal. Studies of long-term effects on cognition have provided conflicting results, with some studies finding no difference between long-term abstainers and never-users and others finding long term deficits. The discrepancies between studies may reflect greater long term effects among heavier users relative to occasional users, and greater duration of effect among those with heavy use as adolescents compared to later in life.<ref>{{cite journal | author = Crean RD, Crane NA, Mason BJ | title = An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions | journal = J Addict Med | volume = 5 | issue = 1 | pages = 1–8 | date = March 2011 | pmid = 21321675 | pmc = 3037578 | doi = 10.1097/ADM.0b013e31820c23fa | url = }}</ref> A second systematic review focused on neuroimaging studies found little evidence supporting an effect of cannabis use on brain structure and function.<ref>{{cite journal | author = Martín-Santos R, Fagundo AB, Crippa JA, Atakan Z, Bhattacharyya S, Allen P, Fusar-Poli P, Borgwardt S, Seal M, Busatto GF, McGuire P | title = Neuroimaging in cannabis use: a systematic review of the literature | journal = Psychol Med | volume = 40 | issue = 3 | pages = 383–98 | date = March 2010 | pmid = 19627647 | doi = 10.1017/S0033291709990729 | url = }}</ref> A 2003 meta analysis concluded that any long term cognitive effects were relatively modest in magnitude and limited to certain aspects of learning and memory.<ref>{{cite journal | author = Grant I, Gonzalez R, Carey CL, Natarajan L, Wolfson T | title = Non-acute (residual) neurocognitive effects of cannabis use: A meta-analytic study | journal = Journal of the International Neuropsychological Society | volume = 9 | issue = 5 | year = 2003 | pmid = 12901774 | doi = 10.1017/S1355617703950016 | laydate = 1 July 2003 | laysummary = http://www.webmd.com/mental-health/news/20030701/heavy-marijuana-use-doesnt-damage-brain | laysource = [[WebMD]] }}</ref>


=== Impact on psychosis ===
=== Impact on psychosis ===
A 2007 meta analysis concluded that cannabis use reduced the average age of onset of psychosis by 2.7 years relative to non-cannabis use.<ref>{{cite journal | author = Large M, Sharma S, Compton MT, Slade T, Nielssen O | title = Cannabis use and earlier onset of psychosis: a systematic meta-analysis | journal = Arch. Gen. Psychiatry | volume = 68 | issue = 6 | pages = 555–61 |date=June 2011 | pmid = 21300939 | doi = 10.1001/archgenpsychiatry.2011.5 | url = }}</ref> A 2005 meta analysis concluded that adolescent use of cannabis increases the risk of psychosis, and that the risk is dose-related.<ref>{{cite journal | author = Semple DM, McIntosh AM, Lawrie SM | title = Cannabis as a risk factor for psychosis: systematic review | journal = J. Psychopharmacol. (Oxford) | volume = 19 | issue = 2 | pages = 187–94 |date=March 2005 | pmid = 15871146 | doi = 10.1177/0269881105049040| url = }}</ref> A 2004 literature review on the subject concluded that cannabis use is associated with a two-fold increase in the risk of psychosis, but that cannabis use is "neither necessary nor sufficient" to cause psychosis.<ref name=Arseneault2004>{{cite journal | author = Arseneault L, Cannon M, Witton J, Murray RM | title = Causal association between cannabis and psychosis: examination of the evidence | journal = The British Journal of Psychiatry | volume = 184 | issue = 2 | pages = 110–117 | year = 2004 | pmid = 14754822 | doi = 10.1192/bjp.184.2.110 }}</ref> A French review from 2009 came to a conclusion that cannabis use, particularly that before age 15, was a factor in the development of schizophrenic disorders.<ref name="Laqueille">{{cite journal|pages=1302–5 |doi=10.1016/j.arcped.2009.03.016 |title=Le cannabis est-il un facteur de vulnérabilité des troubles schizophrènes? |trans_title=Is cannabis is a vulnerability factor of schizophrenic disorders? |year=2009 |last1=Laqueille |first1=X. |journal=Archives de Pédiatrie |volume=16 |issue=9 |registration=yes}}</ref>
A 2007 meta analysis concluded that cannabis use reduced the average age of onset of psychosis by 2.7 years relative to non-cannabis use.<ref>{{cite journal | author = Large M, Sharma S, Compton MT, Slade T, Nielssen O | title = Cannabis use and earlier onset of psychosis: a systematic meta-analysis | journal = Arch. Gen. Psychiatry | volume = 68 | issue = 6 | pages = 555–61 | date = June 2011 | pmid = 21300939 | doi = 10.1001/archgenpsychiatry.2011.5 | url = }}</ref> A 2005 meta analysis concluded that adolescent use of cannabis increases the risk of psychosis, and that the risk is dose-related.<ref>{{cite journal | author = Semple DM, McIntosh AM, Lawrie SM | title = Cannabis as a risk factor for psychosis: systematic review | journal = J. Psychopharmacol. (Oxford) | volume = 19 | issue = 2 | pages = 187–94 | date = March 2005 | pmid = 15871146 | doi = 10.1177/0269881105049040 | url = }}</ref> A 2004 literature review on the subject concluded that cannabis use is associated with a two-fold increase in the risk of psychosis, but that cannabis use is "neither necessary nor sufficient" to cause psychosis.<ref name=Arseneault2004>{{cite journal | author = Arseneault L, Cannon M, Witton J, Murray RM | title = Causal association between cannabis and psychosis: examination of the evidence | journal = The British Journal of Psychiatry | volume = 184 | issue = 2 | pages = 110–117 | year = 2004 | pmid = 14754822 | doi = 10.1192/bjp.184.2.110 }}</ref> A French review from 2009 came to a conclusion that cannabis use, particularly that before age 15, was a factor in the development of schizophrenic disorders.<ref name="Laqueille">{{cite journal | author = Laqueille X | title = Le cannabis est-il un facteur de vulnérabilité des troubles schizophrènes? | journal = Archives de Pédiatrie | volume = 16 | issue = 9 | pages = 1302–5 | year = 2009 | pmid = 19640690 | doi = 10.1016/j.arcped.2009.03.016 | trans_title = Is cannabis is a vulnerability factor of schizophrenic disorders? | registration = yes }}</ref>


Some studies have suggested that cannabis users have a greater risk of developing [[psychosis]] than non-users. This risk is most pronounced in cases with an existing risk of psychotic disorder.<ref>{{cite journal | author = Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G | title = Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review | journal = The Lancet | volume = 370 | issue = 9584 | pages = 319–28 | year = 2007 | pmid = 17662880 | doi = 10.1016/S0140-6736(07)61162-3 | first4 = Thomas RE | first2 = Stanley | first5 = Peter B | first3 = Anne | first6 = Margaret | first7 = Glyn }}</ref><ref>{{cite journal | author = Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van Os J | title = Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people | journal = BMJ | volume = 330 | issue = 7481 | pages = 11–0 | year = 2005 | pmid = 15574485 | pmc = 539839 | doi = 10.1136/bmj.38267.664086.63 | first4 = C | first2 = L | first5 = R | first3 = J | first6 = HU | first7 = J }}</ref> A 2005 paper from the [[Dunedin Multidisciplinary Health and Development Study|Dunedin study]] suggested an increased risk in the development of psychosis linked to polymorphisms in the [[COMT (gene)|COMT]] gene.<ref>{{cite journal | author = Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW | title = Moderation of the Effect of Adolescent-Onset Cannabis Use on Adult Psychosis by a Functional Polymorphism in the Catechol-O-Methyltransferase Gene: Longitudinal Evidence of a Gene X Environment Interaction | journal = Biological Psychiatry | volume = 57 | issue = 10 | pages = 1117–27 | year = 2005 | pmid = 15866551 | doi = 10.1016/j.biopsych.2005.01.026 | first8 = Louise | first12 = Ian W. | first4 = Joseph | first11 = Richie | first2 = Terrie E. | first5 = Robin | first9 = Ben | first10 = Antony | first3 = Mary | first6 = Honalee | first7 = Alan }}</ref> However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on the development of psychosis.<ref name="pmid17978319">{{cite journal | author = Zammit S, Spurlock G, Williams H, Norton N, Williams N, O'Donovan MC, Owen MJ | title = Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use | journal = The British Journal of Psychiatry | volume = 191 | issue = 5 | pages = 402–7 | year = 2007 | pmid = 17978319 | doi = 10.1192/bjp.bp.107.036129 | last5 = Williams | last4 = Norton | last7 = Owen | last6 = O'Donovan | last3 = Williams | last2 = Spurlock | first2 = G | first3 = H | first4 = N | first5 = N | first6 = MC | first7 = MJ | laysummary = http://www.medwire-news.md/47/71003/Psychiatry/Cannabis_and_smoking_gene_links_to_schizophrenia_%E2%80%98unfounded%E2%80%99.html | laysource = MedWireNews }}</ref>
Some studies have suggested that cannabis users have a greater risk of developing [[psychosis]] than non-users. This risk is most pronounced in cases with an existing risk of psychotic disorder.<ref>{{cite journal | author = Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G | title = Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review | journal = The Lancet | volume = 370 | issue = 9584 | pages = 319–28 | year = 2007 | pmid = 17662880 | doi = 10.1016/S0140-6736(07)61162-3 }}</ref><ref>{{cite journal | author = Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van Os J | title = Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people | journal = BMJ | volume = 330 | issue = 7481 | pages = 11–0 | year = 2005 | pmid = 15574485 | pmc = 539839 | doi = 10.1136/bmj.38267.664086.63 }}</ref> A 2005 paper from the [[Dunedin Multidisciplinary Health and Development Study|Dunedin study]] suggested an increased risk in the development of psychosis linked to polymorphisms in the [[COMT (gene)|COMT]] gene.<ref>{{cite journal | author = Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW | title = Moderation of the Effect of Adolescent-Onset Cannabis Use on Adult Psychosis by a Functional Polymorphism in the Catechol-O-Methyltransferase Gene: Longitudinal Evidence of a Gene X Environment Interaction | journal = Biological Psychiatry | volume = 57 | issue = 10 | pages = 1117–27 | year = 2005 | pmid = 15866551 | doi = 10.1016/j.biopsych.2005.01.026 }}</ref> However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on the development of psychosis.<ref name="pmid17978319">{{cite journal | author = Zammit S, Spurlock G, Williams H, Norton N, Williams N, O'Donovan MC, Owen MJ | title = Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use | journal = The British Journal of Psychiatry | volume = 191 | issue = 5 | pages = 402–7 | year = 2007 | pmid = 17978319 | doi = 10.1192/bjp.bp.107.036129 | laysummary = http://www.medwire-news.md/47/71003/Psychiatry/Cannabis_and_smoking_gene_links_to_schizophrenia_%E2%80%98unfounded%E2%80%99.html | laysource = MedWireNews | last2 = Spurlock }}</ref>


A 2008 German review reported that cannabis was a causal factor in some cases of schizophrenia and stressed the need for better education among the public due to increasingly relaxed access to cannabis.<ref>{{cite journal | author = Kawohl W, Rössler W | title = Cannabis and Schizophrenia: new findings in an old debate | journal = Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater | volume = 22 | issue = 4 | pages = 223–9 | year = 2008 | pmid = 19080993 }}</ref>
A 2008 German review reported that cannabis was a causal factor in some cases of schizophrenia and stressed the need for better education among the public due to increasingly relaxed access to cannabis.<ref>{{cite journal | author = Kawohl W, Rössler W | title = Cannabis and Schizophrenia: new findings in an old debate | journal = Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater | volume = 22 | issue = 4 | pages = 223–9 | year = 2008 | pmid = 19080993 }}</ref>


===Other potential long-term effects===
===Other potential long-term effects===
A 2008 [[National Institutes of Health]] study of 19 chronic heavy marijuana users with cardiac and cerebral abnormalities (averaging 28&nbsp;g to 272&nbsp;g (1 to 9+ oz) weekly) and 24 controls found elevated levels of [[Apolipoprotein C3|apolipoprotein C-III]] (apoC-III) in the chronic smokers.<ref>{{cite journal | author = Jayanthi S, Buie S, Moore S, Herning RI, Better W, Wilson NM, Contoreggi C, Cadet JL | title = Heavy marijuana users show increased serum apolipoprotein C-III levels: evidence from proteomic analyses | journal = Molecular Psychiatry | volume = 15 | issue = 1 | pages = 101–112 | year = 2008 | pmid = 18475272 | pmc = 2797551 | doi = 10.1038/mp.2008.50 | first8 = J L | laydate = May 13, 2008 | first4 = R I | first2 = S | first5 = W | laysummary = http://www.reuters.com/article/healthNews/idUSN1231013620080513 | first3 = S | laysource = [[Reuters]] | first6 = N M | first7 = C }}</ref> An increase in apoC-III levels induces the development of [[hypertriglyceridemia]].
A 2008 [[National Institutes of Health]] study of 19 chronic heavy marijuana users with cardiac and cerebral abnormalities (averaging 28&nbsp;g to 272&nbsp;g (1 to 9+ oz) weekly) and 24 controls found elevated levels of [[Apolipoprotein C3|apolipoprotein C-III]] (apoC-III) in the chronic smokers.<ref>{{cite journal | author = Jayanthi S, Buie S, Moore S, Herning RI, Better W, Wilson NM, Contoreggi C, Cadet JL | title = Heavy marijuana users show increased serum apolipoprotein C-III levels: evidence from proteomic analyses | journal = Molecular Psychiatry | volume = 15 | issue = 1 | pages = 101–112 | year = 2008 | pmid = 18475272 | pmc = 2797551 | doi = 10.1038/mp.2008.50 | laysummary = http://www.reuters.com/article/healthNews/idUSN1231013620080513 | laydate = May 13, 2008 | laysource = [[Reuters]] }}</ref> An increase in apoC-III levels induces the development of [[hypertriglyceridemia]].


==== Detection in body fluids ====
==== Detection in body fluids ====
THC, 11-OH-THC and THC-COOH can be detected and quantitated in blood, urine, hair, oral fluid or sweat using a combination of [[immunoassay]] and [[chromatographic]] techniques as part of a drug use testing program or in a forensic investigation of a traffic or other criminal offense or suspicious death.<ref>{{cite journal | author = Schwilke EW, Schwope DM, Karschner EL, Lowe RH, Darwin WD, Kelly DL, Goodwin RS, Gorelick DA, Huestis MA | title = Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous High-Dose Oral THC | journal = Clinical Chemistry | volume = 55 | issue = 12 | pages = 2180–2189 | year = 2009 | pmid = 19833841 | pmc = 3196989 | doi = 10.1373/clinchem.2008.122119 | first8 = D. A. | first4 = R. H. | first2 = D. M. | first5 = W. D. | first9 = M. A. | first3 = E. L. | first6 = D. L. | first7 = R. S. }}</ref><ref>{{cite journal | author = Röhrich J, Schimmel I, Zörntlein S, Becker J, Drobnik S, Kaufmann T, Kuntz V, Urban R | title = Concentrations of Δ<sup>9</sup>-Tetrahydrocannabinol and 11-Nor-9-Carboxytetrahydrocannabinol in Blood and Urine After Passive Exposure to Cannabis Smoke in a Coffee Shop | journal = Journal of Analytical Toxicology | volume = 34 | issue = 4 | pages = 196–203 | year = 2010 | pmid = 20465865 | doi = 10.1093/jat/34.4.196 | first8 = R | first4 = J | first2 = I | first5 = S | first3 = S | first6 = T | first7 = V }}</ref><ref>{{cite book|first1=R. |last1=Baselt |title=Disposition of Toxic Drugs and Chemicals in Man |edition=9th |publisher=Biomedical Publications |location=Seal Beach, CA |year=2011 |pages=1644–8}}</ref>
THC, 11-OH-THC and THC-COOH can be detected and quantitated in blood, urine, hair, oral fluid or sweat using a combination of [[immunoassay]] and [[chromatographic]] techniques as part of a drug use testing program or in a forensic investigation of a traffic or other criminal offense or suspicious death.<ref>{{cite journal | author = Schwilke EW, Schwope DM, Karschner EL, Lowe RH, Darwin WD, Kelly DL, Goodwin RS, Gorelick DA, Huestis MA | title = Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous High-Dose Oral THC | journal = Clinical Chemistry | volume = 55 | issue = 12 | pages = 2180–2189 | year = 2009 | pmid = 19833841 | pmc = 3196989 | doi = 10.1373/clinchem.2008.122119 }}</ref><ref>{{cite journal | author = Röhrich J, Schimmel I, Zörntlein S, Becker J, Drobnik S, Kaufmann T, Kuntz V, Urban R | title = Concentrations of Δ<sup>9</sup>-Tetrahydrocannabinol and 11-Nor-9-Carboxytetrahydrocannabinol in Blood and Urine After Passive Exposure to Cannabis Smoke in a Coffee Shop | journal = Journal of Analytical Toxicology | volume = 34 | issue = 4 | pages = 196–203 | year = 2010 | pmid = 20465865 | doi = 10.1093/jat/34.4.196 }}</ref><ref>{{cite book|first1=R. |last1=Baselt |title=Disposition of Toxic Drugs and Chemicals in Man |edition=9th |publisher=Biomedical Publications |location=Seal Beach, CA |year=2011 |pages=1644–8}}</ref>


=== Interactions ===
=== Interactions ===
The effects of the drug can be reduced by the CB<sub>1</sub> receptor inverse agonist [[rimonabant]] (SR141716A) as well as [[opioid receptor antagonist]]s (opioid blockers) [[naloxone]] and [[naloxonazine]].<ref name="pmid22063718" /><ref name="Lupica 2004">{{cite journal | author = Lupica CR, Riegel AC, Hoffman AF | title = Marijuana and cannabinoid regulation of brain reward circuits | journal = British Journal of Pharmacology | volume = 143 | issue = 2 | pages = 227–34 | year = 2004 | pmid = 15313883 | pmc = 1575338 | doi = 10.1038/sj.bjp.0705931 }}</ref> The [[a7 nicotinic receptor|α<sub>7</sub> nicotinic receptor]] antagonist [[methyllycaconitine]] can block self-administration of THC in rates comparable to the effects of [[varenicline]] on nicotine administration.<ref>{{cite journal | author = Solinas M, Scherma M, Fattore L, Stroik J, Wertheim C, Tanda G, Fratta W, Goldberg SR | title = Nicotinic 7 Receptors as a New Target for Treatment of Cannabis Abuse | journal = Journal of Neuroscience | volume = 27 | issue = 21 | pages = 5615–20 | year = 2007 | pmid = 17522306 | doi = 10.1523/JNEUROSCI.0027-07.2007 | first8 = S. R. | laydate = 22 May 2007 | first4 = J. | first2 = M. | first5 = C. | laysummary = http://www.newscientist.com/article/dn11904-plant-extract-may-block-cannabis-addiction-.html | first3 = L. | laysource = [[New Scientist]] | first6 = G. | first7 = W. }}</ref>
The effects of the drug can be reduced by the CB<sub>1</sub> receptor inverse agonist [[rimonabant]] (SR141716A) as well as [[opioid receptor antagonist]]s (opioid blockers) [[naloxone]] and [[naloxonazine]].<ref name="pmid22063718" /><ref name="Lupica 2004">{{cite journal | author = Lupica CR, Riegel AC, Hoffman AF | title = Marijuana and cannabinoid regulation of brain reward circuits | journal = British Journal of Pharmacology | volume = 143 | issue = 2 | pages = 227–34 | year = 2004 | pmid = 15313883 | pmc = 1575338 | doi = 10.1038/sj.bjp.0705931 }}</ref> The [[a7 nicotinic receptor|α<sub>7</sub> nicotinic receptor]] antagonist [[methyllycaconitine]] can block self-administration of THC in rates comparable to the effects of [[varenicline]] on nicotine administration.<ref>{{cite journal | author = Solinas M, Scherma M, Fattore L, Stroik J, Wertheim C, Tanda G, Fratta W, Goldberg SR | title = Nicotinic 7 Receptors as a New Target for Treatment of Cannabis Abuse | journal = Journal of Neuroscience | volume = 27 | issue = 21 | pages = 5615–20 | year = 2007 | pmid = 17522306 | doi = 10.1523/JNEUROSCI.0027-07.2007 | laysummary = http://www.newscientist.com/article/dn11904-plant-extract-may-block-cannabis-addiction-.html | laydate = 22 May 2007 | laysource = [[New Scientist]] }}</ref>


[[Cannabidiol]], the second most abundant cannabinoid found in cannabis, is an indirect antagonist against cannabinoid agonists; thus reducing the effects of [[anandamide]] and THC agonism on the [[CB1 receptor|CB1]] and [[CB2 receptor]]s.
[[Cannabidiol]], the second most abundant cannabinoid found in cannabis, is an indirect antagonist against cannabinoid agonists; thus reducing the effects of [[anandamide]] and THC agonism on the [[CB1 receptor|CB1]] and [[CB2 receptor]]s.
Line 220: Line 220:
The presence of these specialized cannabinoid receptors in the [[brain]] led researchers to the discovery of [[endocannabinoids]], such as [[anandamide]] and 2-arachidonoyl glyceride ([[2-AG]]). THC targets receptors in a manner far less selective than endocannabinoid molecules released during [[retrograde signaling]], as the drug has a relatively low cannabinoid receptor efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy.<ref name="pmid17828291">{{cite journal | author = Pertwee RG | title = The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin | journal = British Journal of Pharmacology | volume = 153 | issue = 2 | pages = 199–215 | year = 2008 | pmid = 17828291 | pmc = 2219532 | doi = 10.1038/sj.bjp.0707442 }}</ref> THC is a [[lipophilic]] molecule<ref>{{cite journal | author = Rashidi H, Akhtar MT, van der Kooy F, Verpoorte R, Duetz WA | title = Hydroxylation and Further Oxidation of Δ9-Tetrahydrocannabinol by Alkane-Degrading Bacteria | journal = Appl Environ Microbiol | volume = 75 | issue = 22 | pages = 7135–7141 | date = November 2009 | pmid = 19767471 | pmc = 2786519 | doi = 10.1128/AEM.01277-09 | url = http://aem.asm.org/cgi/pmidlookup?view=long&pmid=19767471 | quote = Δ9-THC and many of its derivatives are highly lipophilic and poorly water soluble. Calculations of the n-octanol/water partition coefficient (Ko/w) of Δ9-THC at neutral pH vary between 6,000, using the shake flask method, and 9.44 × 106, by reverse-phase high-performance liquid chromatography estimation. | format = PDF }}</ref> and may bind non-specifically to a variety of entities in the brain and body, such as [[adipose tissue]] (fat).<ref>{{cite journal | author = Ashton CH | title = Pharmacology and effects of cannabis: a brief review | journal = Br J Psychiatry | volume = 178 | pages = 101–106 | date = February 2001 | pmid = 11157422 | doi = 10.1192/bjp.178.2.101 | url = http://bjp.rcpsych.org/content/178/2/101.full | quote = Because they are extremely lipid soluble, cannabinoids accumulate in fatty tissues, reaching peak concentrations in 4–5 days. They are then slowly released back into other body compartments, including the brain. ... Within the brain, THC and other cannabinoids are differentially distributed. High concentrations are reached in neocortical, limbic, sensory and motor areas. }}</ref><ref>{{cite journal | author = Huestis MA | title = Human cannabinoid pharmacokinetics | journal = Chem Biodivers | volume = 4 | issue = 8 | pages = 1770–804 | date = August 2007 | pmid = 17712819 | pmc = 2689518 | doi = 10.1002/cbdv.200790152 | url = http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/17712819/ | quote = THC is highly lipophilic and initially taken up by tissues that are highly perfused, such as the lung, heart, brain, and liver. }}</ref>
The presence of these specialized cannabinoid receptors in the [[brain]] led researchers to the discovery of [[endocannabinoids]], such as [[anandamide]] and 2-arachidonoyl glyceride ([[2-AG]]). THC targets receptors in a manner far less selective than endocannabinoid molecules released during [[retrograde signaling]], as the drug has a relatively low cannabinoid receptor efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy.<ref name="pmid17828291">{{cite journal | author = Pertwee RG | title = The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin | journal = British Journal of Pharmacology | volume = 153 | issue = 2 | pages = 199–215 | year = 2008 | pmid = 17828291 | pmc = 2219532 | doi = 10.1038/sj.bjp.0707442 }}</ref> THC is a [[lipophilic]] molecule<ref>{{cite journal | author = Rashidi H, Akhtar MT, van der Kooy F, Verpoorte R, Duetz WA | title = Hydroxylation and Further Oxidation of Δ9-Tetrahydrocannabinol by Alkane-Degrading Bacteria | journal = Appl Environ Microbiol | volume = 75 | issue = 22 | pages = 7135–7141 | date = November 2009 | pmid = 19767471 | pmc = 2786519 | doi = 10.1128/AEM.01277-09 | url = http://aem.asm.org/cgi/pmidlookup?view=long&pmid=19767471 | quote = Δ9-THC and many of its derivatives are highly lipophilic and poorly water soluble. Calculations of the n-octanol/water partition coefficient (Ko/w) of Δ9-THC at neutral pH vary between 6,000, using the shake flask method, and 9.44 × 106, by reverse-phase high-performance liquid chromatography estimation. | format = PDF }}</ref> and may bind non-specifically to a variety of entities in the brain and body, such as [[adipose tissue]] (fat).<ref>{{cite journal | author = Ashton CH | title = Pharmacology and effects of cannabis: a brief review | journal = Br J Psychiatry | volume = 178 | pages = 101–106 | date = February 2001 | pmid = 11157422 | doi = 10.1192/bjp.178.2.101 | url = http://bjp.rcpsych.org/content/178/2/101.full | quote = Because they are extremely lipid soluble, cannabinoids accumulate in fatty tissues, reaching peak concentrations in 4–5 days. They are then slowly released back into other body compartments, including the brain. ... Within the brain, THC and other cannabinoids are differentially distributed. High concentrations are reached in neocortical, limbic, sensory and motor areas. }}</ref><ref>{{cite journal | author = Huestis MA | title = Human cannabinoid pharmacokinetics | journal = Chem Biodivers | volume = 4 | issue = 8 | pages = 1770–804 | date = August 2007 | pmid = 17712819 | pmc = 2689518 | doi = 10.1002/cbdv.200790152 | url = http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/17712819/ | quote = THC is highly lipophilic and initially taken up by tissues that are highly perfused, such as the lung, heart, brain, and liver. }}</ref>


THC, similarly to cannabidiol, albeit less potently, is an [[allosteric modulator]] of the [[μ-opioid receptor|μ-]] and [[δ-opioid receptor]]s.<ref name="pmid16489449">{{cite journal | author = Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E | title = Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors | journal = Naunyn Schmiedebergs Arch. Pharmacol. | volume = 372 | issue = 5 | pages = 354–61 |date=February 2006 | pmid = 16489449 | doi = 10.1007/s00210-006-0033-x | url = }}</ref>
THC, similarly to cannabidiol, albeit less potently, is an [[allosteric modulator]] of the [[μ-opioid receptor|μ-]] and [[δ-opioid receptor]]s.<ref name="pmid16489449">{{cite journal | author = Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E | title = Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors | journal = Naunyn Schmiedebergs Arch. Pharmacol. | volume = 372 | issue = 5 | pages = 354–61 | date = February 2006 | pmid = 16489449 | doi = 10.1007/s00210-006-0033-x | url = }}</ref>


=== Pharmacokinetics ===
=== Pharmacokinetics ===
Line 227: Line 227:
== Biosynthesis ==
== Biosynthesis ==
[[File:THC biosynthesis.png|thumb|Biosynthesis of THC]]
[[File:THC biosynthesis.png|thumb|Biosynthesis of THC]]
In the [[cannabis]] plant, THC occurs mainly as [[tetrahydrocannabinolic acid]] (THCA, 2-COOH-THC). [[Geranyl pyrophosphate]] and [[olivetol]]ic acid react, catalysed by an [[enzyme]] to produce [[cannabigerol]]ic acid,<ref name="pmid9607329">{{cite journal | author = Fellermeier M, Zenk MH | title = Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid, the precursor of tetrahydrocannabinol | journal = FEBS Letters | volume = 427 | issue = 2 | pages = 283–5 | year = 1998 | pmid = 9607329 | doi = 10.1016/S0014-5793(98)00450-5 }}</ref> which is cyclized by the enzyme [[THC acid synthase]] to give THCA. Over time, or when heated, THCA is [[decarboxylation|decarboxylated]], producing THC. The pathway for THCA biosynthesis is similar to that which produces the bitter acid [[humulone]] in [[hops]].<ref>{{cite journal | author = Marks MD, Tian L, Wenger JP, Omburo SN, Soto-Fuentes W, He J, Gang DR, Weiblen GD, Dixon RA | title = Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa | journal = Journal of Experimental Botany | volume = 60 | issue = 13 | pages = 3715–26 | year = 2009 | pmid = 19581347 | pmc = 2736886 | doi = 10.1093/jxb/erp210 | first8 = G. D. | first4 = S. N. | first2 = L. | first5 = W. | first9 = R. A. | first3 = J. P. | first6 = J. | first7 = D. R. }}</ref><ref>{{cite journal | author = Baker PB, Taylor BJ, Gough TA | title = The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products | journal = J Pharm Pharmacol. | volume = 33 | issue = 6 | pages = 369–72 | date = June 1981 | pmid = 6115009 | doi = 10.1111/j.2042-7158.1981.tb13806.x | last3 = Gough | last2 = Taylor | first2 = BJ | first3 = TA }}</ref>
In the [[cannabis]] plant, THC occurs mainly as [[tetrahydrocannabinolic acid]] (THCA, 2-COOH-THC). [[Geranyl pyrophosphate]] and [[olivetol]]ic acid react, catalysed by an [[enzyme]] to produce [[cannabigerol]]ic acid,<ref name="pmid9607329">{{cite journal | author = Fellermeier M, Zenk MH | title = Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid, the precursor of tetrahydrocannabinol | journal = FEBS Letters | volume = 427 | issue = 2 | pages = 283–5 | year = 1998 | pmid = 9607329 | doi = 10.1016/S0014-5793(98)00450-5 }}</ref> which is cyclized by the enzyme [[THC acid synthase]] to give THCA. Over time, or when heated, THCA is [[decarboxylation|decarboxylated]], producing THC. The pathway for THCA biosynthesis is similar to that which produces the bitter acid [[humulone]] in [[hops]].<ref>{{cite journal | author = Marks MD, Tian L, Wenger JP, Omburo SN, Soto-Fuentes W, He J, Gang DR, Weiblen GD, Dixon RA | title = Identification of candidate genes affecting Δ9-tetrahydrocannabinol biosynthesis in Cannabis sativa | journal = Journal of Experimental Botany | volume = 60 | issue = 13 | pages = 3715–26 | year = 2009 | pmid = 19581347 | pmc = 2736886 | doi = 10.1093/jxb/erp21 }}</ref><ref>{{cite journal | author = Baker PB, Taylor BJ, Gough TA | title = The tetrahydrocannabinol and tetrahydrocannabinolic acid content of cannabis products | journal = J Pharm Pharmacol. | volume = 33 | issue = 6 | pages = 369–72 | date = June 1981 | pmid = 6115009 | doi = 10.1111/j.2042-7158.1981.tb13806.x }}</ref>


==Chemical synthesis==
==Chemical synthesis==
Line 236: Line 236:
Optically active [[verbenol]] can be used instead of [[citral]].
Optically active [[verbenol]] can be used instead of [[citral]].


Please note the attached citations:<ref>{{cite journal | author = Razdan RK | title = Hashish. V. A stereospecific synthesis of (-)-.DELTA.1-and (-).DELTA.1(6)-tetrahydrocannabinols | journal = Journal of the American Chemical Society | volume = 92 | issue = 20 | pages = 6061–6062 | date = 1970 | doi = 10.1021/ja00723a044 }}</ref><ref>{{cite journal | author = Petrzilka T | title = Synthese von Haschisch-Inhaltsstoffen. 4. Mitteilung | journal = Helvetica Chimica Acta | volume = 52 | issue = 4 | pages = 1102–1134 | date = 1969 | doi = 10.1002/hlca.19690520427 }}</ref><ref>{{cite journal | last1 = Jen T | title = Total synthesis of .DELTA.8-(.DELTA.1(6)-tetrahydrocannabinol, a biologically active constituent of hashish (marijuana) | journal = Journal of the American Chemical Society | volume = 89 | issue = 17 | pages = 4551–4552 | date = 1967 | doi = 10.1021/ja00993a071 }}</ref>
Please note the attached citations:<ref>{{Cite doi|10.1021/ja00723a044}}</ref><ref>{{Cite doi|10.1002/hlca.19690520427}}</ref><ref>{{Cite doi|10.1021/ja00993a071}}</ref>


== Marinol ==<!-- linked from "Marinol" and "Drobaninol" -->
== Marinol ==<!-- linked from "Marinol" and "Drobaninol" -->

Revision as of 20:16, 5 October 2014

Tetrahydrocannabinol
Clinical data
Other namesDronabinol
License data
Dependence
liability
8–10% (Relatively low risk of tolerance)[1]
Routes of
administration
Orally, local/topical, transdermal sublingual, smoked (or vaporized)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability10–35% (inhalation), 6–20% (oral)[3]
Protein binding97–99%[3][4][5]
MetabolismMostly hepatic by CYP2C[3]
Elimination half-life1.6–59 h,[3] 25–36 h (orally administered dronabinol)
Excretion65–80% (faeces), 20–35% (urine) as acid metabolites[3]
Identifiers
  • (−)-(6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.153.676 Edit this at Wikidata
Chemical and physical data
FormulaC21H30O2
Molar mass314.469 g/mol g·mol−1
3D model (JSmol)
Specific rotation-152° (ethanol)
Boiling point250 °C (482 °F)
(range: 250–400 °C)[6]
Solubility in water0.0028,[7] (23 °C) mg/mL (20 °C)
  • CCCCCc1cc(c2c(c1)OC([C@H]3[C@H]2C=C(CC3)C)(C)C)O
  • InChI=1S/C21H30O2/c1-5-6-7-8-15-12-18(22)20-16-11-14(2)9-10-17(16)21(3,4)23-19(20)13-15/h11-13,16-17,22H,5-10H2,1-4H3/t16-,17-/m1/s1 checkY
  • Key:CYQFCXCEBYINGO-IAGOWNOFSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Tetrahydrocannabinol (THC), or more precisely its main isomer (−)-trans9-tetrahydrocannabinol ( (6aR,10aR)-delta-9-tetrahydrocannabinol), is the principal psychoactive constituent (or cannabinoid) of the cannabis plant. First isolated in 1964 by Israeli scientists Raphael Mechoulam and Yechiel Gaoni at the Weizmann Institute of Science[8][9][10] it is a water-clear glassy solid when cold, which becomes viscous and sticky if warmed. A pharmaceutical formulation of (−)-trans9-tetrahydrocannabinol, known by its INN dronabinol, is available by prescription in the U.S. and Canada under the brand name Marinol. An aromatic terpenoid, THC has a very low solubility in water, but good solubility in most organic solvents, specifically lipids and alcohols.[7]

Like most pharmacologically-active secondary metabolites of plants, THC in cannabis is assumed to be involved in self-defense, perhaps against herbivores.[11] THC also possesses high UV-B (280–315 nm) absorption properties, which, it has been speculated, could protect the plant from harmful UV radiation exposure.[12][13][14]

Tetrahydrocannabinol with double bond isomers and their stereoisomers is one of only three cannabinoids scheduled by Convention on Psychotropic Substances (the other two are dimethylheptylpyran and parahexyl). Cannabis as a plant is scheduled by the Single Convention on Narcotic Drugs (Schedule I and IV).

Effects

THC has mild to moderate analgesic effects, and cannabis can be used to treat pain by altering transmitter release on dorsal root ganglion of the spinal cord and in the periaqueductal gray.[15] Other effects include relaxation, alteration of visual, auditory, and olfactory senses, fatigue, and appetite stimulation. THC has marked antiemetic properties. It may acutely reduce aggression and increase aggression during withdrawal.[16]

Due to its partial agonistic activity, THC appears to result in greater downregulation of cannabinoid receptors than endocannabinoids, further limiting its efficacy over other cannabinoids. While tolerance may limit the maximal effects of certain drugs, evidence suggests that tolerance develops irregularly for different effects with greater resistance for primary over side-effects, and may actually serve to enhance the drug's therapeutic window.[17] However, this form of tolerance appears to be irregular throughout mouse brain areas. THC, as well as other cannabinoids that contain a phenol group, possesses mild antioxidant activity sufficient to protect neurons against oxidative stress, such as that produced by glutamate-induced excitotoxicity.[18]

Appetite and taste

It has long been known that, in humans, cannabis increases appetite and consumption of food. The mechanism for appetite stimulation in subjects is believed to result from activity in the gastro-hypothalamic axis. CB1 activity in the hunger centers in the hypothalamus increases the palatability of food when levels of a hunger hormone ghrelin increase prior to consuming a meal. After chyme is passed into the duodenum, signaling hormones such as cholecystokinin and leptin are released, causing reduction in gastric emptying and transmission of satiety signals to the hypothalamus. Cannabinoid activity is reduced through the satiety signals induced by leptin release.

A study in mice suggested that based on the connection between palatable food and stimulation of dopamine (DA) transmission in the shell of the nucleus accumbens (NAc), cannabis may not only stimulate taste, but possibly the hedonic (pleasure) value of food as well. The study later demonstrates habitual use of THC lessening this heightened pleasure response, indicating a possible similarity in humans.[19] The inconsistency between DA habituation and enduring appetite observed after THC application suggests that cannabis-induced appetite stimulation is not only mediated by enhanced pleasure from palatable food, but through THC stimulation of another appetitive response as well.

Chemistry

Discovery and structure identification

The discovery of THC by team of researchers from Hebrew University Pharmacy School was first described in "Isolation, structure and partial synthesis of an active constituent of hashish", published in the Journal of the American Chemical Society in 1964.[8] Research was also published in the academic journal Science, with "Marijuana chemistry" by Raphael Mechoulam in June 1970,[20] In the latter, the team of researchers from Hebrew University and Tel Aviv University experimented on monkeys to isolate the active compounds in hashish. Their results provided evidence that, except for tetrahydrocannabinol, no other major active compounds were present in hashish.

Isomerism

Dibenzopyran and monoterpenoid numbering of tetrahydrocannabinol derivatives
Dibenzopyran and monoterpenoid numbering of tetrahydrocannabinol derivatives
7 double bond isomers and their 30 stereoisomers
Dibenzopyran numbering Monoterpenoid numbering Number of stereoisomers Natural occurrence Convention on Psychotropic Substances Schedule Structure
Short name Chiral centers Full name Short name Chiral centers
Δ6a,7-tetrahydrocannabinol 9 and 10a 8,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol Δ4-tetrahydrocannabinol 1 and 3 4 No Schedule I
Δ7-tetrahydrocannabinol 6a, 9 and 10a 6a,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol Δ5-tetrahydrocannabinol 1, 3 and 4 8 No Schedule I
Δ8-tetrahydrocannabinol 6a and 10a 6a,7,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol Δ6-tetrahydrocannabinol 3 and 4 4 Yes Schedule I
Δ9,11-tetrahydrocannabinol 6a and 10a 6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-9-methylene-3-pentyl-6H-dibenzo[b,d]pyran-1-ol Δ1,7-tetrahydrocannabinol 3 and 4 4 No Schedule I
Δ9-tetrahydrocannabinol 6a and 10a 6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol Δ1-tetrahydrocannabinol 3 and 4 4 Yes Schedule II
Δ10-tetrahydrocannabinol 6a and 9 6a,7,8,9-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol Δ2-tetrahydrocannabinol 1 and 4 4 No Schedule I
Δ6a,10a-tetrahydrocannabinol 9 7,8,9,10-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol Δ3-tetrahydrocannabinol 1 2 No Schedule I
4 stereoisomers of Δ9-tetrahydrocannabinol
Names Description Natural occurrence Structure
(−)-trans9-tetrahydrocannabinol (6aR,10aR)-Δ9-tetrahydrocannabinol levorotary trans Yes
(−)-cis9-tetrahydrocannabinol (6aS,10aR)-Δ9-tetrahydrocannabinol levorotary cis Yes
(+)-trans9-tetrahydrocannabinol (6aS,10aS)-Δ9-tetrahydrocannabinol dextrorotary trans No
(+)-cis9-tetrahydrocannabinol (6aR,10aS)-Δ9-tetrahydrocannabinol dextrorotary cis No

Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6H-benzo[c]chromen-1-ol.

  • Further reading on cannabanoid isomerism: John C. Leffingwell (May 2003). "Chirality & Bioactivity I.: Pharmacology" (PDF). pp. 18–20. Retrieved 12 January 2014.
3D rendering of the THC molecule
A hybrid Cannabis strain (White Widow) flower coated with trichomes, which contain more THC than any other part of the plant
Closeup of THC-filled trichomes on a Cannabis sativa leaf

Medical uses

In April 2014 the American Academy of Neurology published a systematic review of the efficacy and safety of medical marijuana and marijuana-derived products in certain neurological disorders.[21] The review identified 34 studies meeting inclusion criteria, of which 8 were rated as Class I quality. The study found evidence supporting the effectiveness of cannabis extracts and THC in treating certain symptoms of multiple sclerosis, but found insufficient evidence to determine the effectiveness of cannabis products in treating several other neurological diseases.

Multiple sclerosis symptoms

Spasticity. Based on the results of 3 high quality trials and 5 of lower quality, oral cannabis extract was rated as effective, and THC as probably effective, for improving patient's subjective experience of spasticity. Oral cannabis extract and THC both were rated as possibly effective for improving objective measures of spasticity.[21]
Centrally mediated pain and painful spasms. Based on the results of 4 high quality trials and 4 low quality trials, oral cannabis extract was rated as effective, and THC as probably effective in treating central pain and painful spasms.[21]
Bladder dysfunction. Based on a single high quality study, oral cannabis extract and THC were rated as probably ineffective for controlling bladder complaints in multiple sclerosis[21]

Neurodegenerative disorders

Huntington disease. No reliable conclusions could be drawn regarding the effectiveness of THC or oral cannabis extract in treating the symptoms of Huntington disease as the available trials were too small to reliably detect any difference[21]
Parkinson disease. Based on a single study, oral cannabis extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson disease.[21]
Alzheimer's disease. A 2011 Cochrane Review found insufficient evidence to conclude whether cannabis products have any utility in the treatment of Alzheimer's disease.[22]

Other neurological disorders

Tourette syndrome. The available data was determined to be insufficient to allow reliable conclusions to be drawn regarding the effectiveness of oral cannabis extract or THC in controlling tics.[21]
Cervical dystonia. Insufficient data was available to assess the effectiveness of oral cannabis extract of THC in treating cervical dystonia.[21]
Epilepsy. Data was considered insufficient to judge the utility of cannabis products in reducing seizure frequency or severity.[21]

Other studies in humans

Evidence suggests that THC helps alleviate symptoms suffered both by AIDS patients, and by cancer patients undergoing chemotherapy, by increasing appetite and decreasing nausea.[23][24][25][26] It has also been shown to assist some glaucoma patients[citation needed] by reducing pressure within the eye, and is used in the form of cannabis by a number of multiple sclerosis patients, who use it to alleviate neuropathic pain and spasticity. The National Multiple Sclerosis Society is currently supporting further research into these uses.[27] Studies in humans have been limited by federal and state laws criminalizing marijuana.

In August 2009 a phase IV clinical trial by the Hadassah Medical Center in Jerusalem, Israel started to investigate the effects of THC on post-traumatic stress disorders.[28]

Research on THC has shown that the cannabinoid receptors are responsible for mediated inhibition of dopamine release in the retina.[29]

Several studies have been conducted with spinal injury patients and THC. Decreased tremor occurred in 2/5 patients in a 1986 double-blind, placebo-controlled crossover study.[30]

Studies in animals and in vitro

A two-year study in which rats and mice were force-fed tetrahydrocannabinol dissolved in corn oil showed reduced body mass, enhanced survival rates, and decreased tumor incidences in several sites, mainly organs under hormonal control. It also caused testicular atrophy and uterine and ovarian hypoplasia, as well as hyperactivity and convulsions immediately after administration, of which the onset and frequency were dose related.[31]

Research in rats indicates that THC prevents hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures.[32] In mice low doses of Δ9-THC reduces the progression of atherosclerosis.[33]

Instead, recent studies with synthetic cannabinoids show that activation of CB1 receptors can facilitate neurogenesis,[34] as well as neuroprotection, in animals[35] This, along with research into the CB2 receptor (throughout the immune system), has given the case for medical marijuana more support.[36][37] THC is both a CB1 and CB2 agonist.[38]

Adverse effects

Acute toxicity

There has never been a documented human fatality solely from overdosing on tetrahydrocannabinol or cannabis in its natural form.[39] However, numerous reports have suggested an association of cannabis smoking with an increased risk of myocardial infarction.[40][41] Information about the toxicity of THC is primarily based on results from animal studies. The toxicity depends on the route of administration and the laboratory animal.

The estimated lethal dose of intravenous dronabinol in humans is 30 mg/kg,[42] meaning lethality is unlikely. The typical medicinal dosage administered is two 2.5 mg capsules daily; for an 80 kg man (~170 lb). A lethal dose for such a person would be 960 of those capsules infused intravenously. Non-fatal overdoses have occurred: "Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules."[42]

A meta analysis of cannabis and THC clinical trials conducted by the American Academy of Neurology found that of 1619 persons treated with cannabis products (including some treated with smoked cannabis and nabiximols), 6.9% discontinued due to side effects, compared to 2.2% of 1,118 treated with placebo. Detailed information regarding side effects was not available from all trials, but nausea, increased weakness, behavioral or mood changes, suicidal ideation, hallucinations, dizziness, and vasovagal symptoms, fatigue, and feelings of intoxication were each described as side effects in at least 2 trials. There was a single death rated by the investigator as "possibly related" to treatment. This person had a seizure followed by aspiration pneumonia. The paper does not describe whether this was one of the patients from the epilepsy trials.[21]

Cognitive effects

Its status as an illegal drug in most countries can make research difficult; for instance in the United States where the National Institute on Drug Abuse was the only legal source of cannabis for researchers until it recently became legalized in Colorado and Washington state.[43]

A 2011 systematic review evaluated published studies of the acute and long-term cognitive effects of cannabis. THC intoxication is well established to impair cognitive functioning on an acute basis, including effects on the ability to plan, organize, solve problems, make decisions, and control impulses. The extent of this impact may be greater in novice users, and paradoxically, those habituated to high level ingestion may have reduced cognition during withdrawal. Studies of long-term effects on cognition have provided conflicting results, with some studies finding no difference between long-term abstainers and never-users and others finding long term deficits. The discrepancies between studies may reflect greater long term effects among heavier users relative to occasional users, and greater duration of effect among those with heavy use as adolescents compared to later in life.[44] A second systematic review focused on neuroimaging studies found little evidence supporting an effect of cannabis use on brain structure and function.[45] A 2003 meta analysis concluded that any long term cognitive effects were relatively modest in magnitude and limited to certain aspects of learning and memory.[46]

Impact on psychosis

A 2007 meta analysis concluded that cannabis use reduced the average age of onset of psychosis by 2.7 years relative to non-cannabis use.[47] A 2005 meta analysis concluded that adolescent use of cannabis increases the risk of psychosis, and that the risk is dose-related.[48] A 2004 literature review on the subject concluded that cannabis use is associated with a two-fold increase in the risk of psychosis, but that cannabis use is "neither necessary nor sufficient" to cause psychosis.[49] A French review from 2009 came to a conclusion that cannabis use, particularly that before age 15, was a factor in the development of schizophrenic disorders.[50]

Some studies have suggested that cannabis users have a greater risk of developing psychosis than non-users. This risk is most pronounced in cases with an existing risk of psychotic disorder.[51][52] A 2005 paper from the Dunedin study suggested an increased risk in the development of psychosis linked to polymorphisms in the COMT gene.[53] However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on the development of psychosis.[54]

A 2008 German review reported that cannabis was a causal factor in some cases of schizophrenia and stressed the need for better education among the public due to increasingly relaxed access to cannabis.[55]

Other potential long-term effects

A 2008 National Institutes of Health study of 19 chronic heavy marijuana users with cardiac and cerebral abnormalities (averaging 28 g to 272 g (1 to 9+ oz) weekly) and 24 controls found elevated levels of apolipoprotein C-III (apoC-III) in the chronic smokers.[56] An increase in apoC-III levels induces the development of hypertriglyceridemia.

Detection in body fluids

THC, 11-OH-THC and THC-COOH can be detected and quantitated in blood, urine, hair, oral fluid or sweat using a combination of immunoassay and chromatographic techniques as part of a drug use testing program or in a forensic investigation of a traffic or other criminal offense or suspicious death.[57][58][59]

Interactions

The effects of the drug can be reduced by the CB1 receptor inverse agonist rimonabant (SR141716A) as well as opioid receptor antagonists (opioid blockers) naloxone and naloxonazine.[19][60] The α7 nicotinic receptor antagonist methyllycaconitine can block self-administration of THC in rates comparable to the effects of varenicline on nicotine administration.[61]

Cannabidiol, the second most abundant cannabinoid found in cannabis, is an indirect antagonist against cannabinoid agonists; thus reducing the effects of anandamide and THC agonism on the CB1 and CB2 receptors.

Mechanism of action

The pharmacological actions of THC result from its partial agonist activity at the cannabinoid receptor CB1 (Ki=10nM[62]), located mainly in the central nervous system, and the CB2 receptor (Ki=24nM[62]), mainly expressed in cells of the immune system.[18] The psychoactive effects of THC are primarily mediated by its activation of CB1G-protein coupled receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyclase.[15]

The presence of these specialized cannabinoid receptors in the brain led researchers to the discovery of endocannabinoids, such as anandamide and 2-arachidonoyl glyceride (2-AG). THC targets receptors in a manner far less selective than endocannabinoid molecules released during retrograde signaling, as the drug has a relatively low cannabinoid receptor efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy.[17] THC is a lipophilic molecule[63] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).[64][65]

THC, similarly to cannabidiol, albeit less potently, is an allosteric modulator of the μ- and δ-opioid receptors.[66]

Pharmacokinetics

THC is metabolized mainly to 11-OH-THC by the body. This metabolite is still psychoactive and is further oxidized to 11-nor-9-carboxy-THC (THC-COOH). In humans and animals, more than 100 metabolites could be identified, but 11-OH-THC and THC-COOH are the dominating metabolites. Metabolism occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4.[67] More than 55% of THC is excreted in the feces and ~20% in the urine. The main metabolite in urine is the ester of glucuronic acid and THC-COOH and free THC-COOH. In the feces, mainly 11-OH-THC was detected.[68]

Biosynthesis

Biosynthesis of THC

In the cannabis plant, THC occurs mainly as tetrahydrocannabinolic acid (THCA, 2-COOH-THC). Geranyl pyrophosphate and olivetolic acid react, catalysed by an enzyme to produce cannabigerolic acid,[69] which is cyclized by the enzyme THC acid synthase to give THCA. Over time, or when heated, THCA is decarboxylated, producing THC. The pathway for THCA biosynthesis is similar to that which produces the bitter acid humulone in hops.[70][71]

Chemical synthesis

Total chemical syntheses largely depend on carefully controlled acid catalyzed condensation of selected monoterpenes with olivetol. If citral is used as start material only the racemic product is formed. The condensation is acid catalyzed, but 0.0005 N hydrogen chloride only affords a 12% yield. 1% boron trifluoride is used as the catalyst.

Since isomerization of Δ1THC to virtually inactive Δ6THC takes place readily in acid or upon heating, the cyclizations must be carefully controlled.

Optically active verbenol can be used instead of citral.

Please note the attached citations:[72][73][74]

Marinol

Dronabinol is the INN for a pure isomer of THC, (–)-trans9-tetrahydrocannabinol,[75] which is the main isomer found in cannabis. It is sold as Marinol (a registered trademark of Solvay Pharmaceuticals). Dronabinol is also marketed, sold, and distributed by PAR Pharmaceutical Companies under the terms of a license and distribution agreement with SVC pharma LP, an affiliate of Rhodes Technologies. Synthesized THC may be generally referred to as dronabinol. It is available as a prescription drug (under Marinol[76]) in several countries including the United States and Germany. In the United States, Marinol is a Schedule III drug, available by prescription, considered to be non-narcotic and to have a low risk of physical or mental dependence. Efforts to get cannabis rescheduled as analogous to Marinol have not succeeded thus far, though a 2002 petition has been accepted by the DEA. As a result of the rescheduling of Marinol from Schedule II to Schedule III, refills are now permitted for this substance. Marinol has been approved by the U.S. Food and Drug Administration (FDA) in the treatment of anorexia in AIDS patients, as well as for refractory nausea and vomiting of patients undergoing chemotherapy, which has raised much controversy[citation needed] as to why natural THC is still a schedule I drug.[77]

An overdose usually presents with lethargy, decreased motor coordination, slurred speech, and postural hypotension. The FDA estimates the lethal human dose of intravenous dronabinol to be 30 mg/kg (2100 mg/ 70 kg).[78]

An analog of dronabinol, nabilone, is available commercially in Canada under the trade name Cesamet, manufactured by Valeant Pharmaceuticals. Cesamet has also received FDA approval and began marketing in the U.S. in 2006. Nabilone is a Schedule II drug.[79]

Comparisons with medical marijuana

Female cannabis plants contain more than 60 cannabinoids, including cannabidiol (CBD), thought to be the major anticonvulsant that helps multiple sclerosis patients;[80] and cannabichromene (CBC), an anti-inflammatory which may contribute to the pain-killing effect of cannabis.[81]

It takes over one hour for Marinol to reach full systemic effect,[82] compared to seconds or minutes for smoked or vaporized cannabis.[83] Some patients accustomed to inhaling just enough cannabis smoke to manage symptoms have complained of too-intense intoxication from Marinol's predetermined dosages[citation needed]. Many patients have said that Marinol produces a more acute psychedelic effect than cannabis, and it has been speculated that this disparity can be explained by the moderating effect of the many non-THC cannabinoids present in cannabis.[citation needed] For that reason, alternative THC-containing medications based on botanical extracts of the cannabis plant such as nabiximols are being developed. Mark Kleiman, director of the Drug Policy Analysis Program at UCLA's School of Public Affairs said of Marinol, "It wasn't any fun and made the user feel bad, so it could be approved without any fear that it would penetrate the recreational market, and then used as a club with which to beat back the advocates of whole cannabis as a medicine."[84] Mr. Kleiman's opinion notwithstanding, clinical trials comparing the use of cannabis extracts with Marinol in the treatment of cancer cachexia have demonstrated equal efficacy and well-being among patients in the two treatment arms.[85] United States federal law currently registers dronabinol as a Schedule III controlled substance, but all other cannabinoids remain Schedule I, except synthetics like nabilone.[86]

Regulatory history

Since at least 1986, the trend has been for THC in general, and especially the Marinol preparation, to be downgraded to less and less stringently-controlled schedules of controlled substances, in the U.S. and throughout the rest of the world.

On May 13, 1986, the Drug Enforcement Administration (DEA) issued a Final Rule and Statement of Policy authorizing the "Rescheduling of Synthetic Dronabinol in Sesame Oil and Encapsulated in Soft Gelatin Capsules From Schedule I to Schedule II" (DEA 51 FR 17476-78). This permitted medical use of Marinol, albeit with the severe restrictions associated with Schedule II status.[87] For instance, refills of Marinol prescriptions were not permitted. At its 1045th meeting, on April 29, 1991, the Commission on Narcotic Drugs, in accordance with article 2, paragraphs 5 and 6, of the Convention on Psychotropic Substances, decided that Δ9-tetrahydrocannabinol (also referred to as Δ9-THC) and its stereochemical variants should be transferred from Schedule I to Schedule II of that Convention. This released Marinol from the restrictions imposed by Article 7 of the Convention (See also United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances).[citation needed]

An article published in the April–June 1998 issue of the Journal of Psychoactive Drugs found that "Healthcare professionals have detected no indication of scrip-chasing or doctor-shopping among the patients for whom they have prescribed dronabinol". The authors state that Marinol has a low potential for abuse.[88]

In 1999, Marinol was rescheduled from Schedule II to III of the Controlled Substances Act, reflecting a finding that THC had a potential for abuse less than that of cocaine and heroin. This rescheduling constituted part of the argument for a 2002 petition for removal of cannabis from Schedule I of the Controlled Substances Act, in which petitioner Jon Gettman noted, "Cannabis is a natural source of dronabinol (THC), the ingredient of Marinol, a Schedule III drug. There are no grounds to schedule cannabis in a more restrictive schedule than Marinol".[89]

At its 33rd meeting, in 2003, the World Health Organization Expert Committee on Drug Dependence recommended transferring THC to Schedule IV of the Convention, citing its medical uses and low abuse potential.[90]

See also

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Further reading

External links